During the early to mid 1990s, Marg played roles in Michael Bortman's adaptation of Robert Boswell's novel, Crooked Hearts (1991; with Peter Berg, Vincent D'Onofrio, Jennifer Jason Leigh, Noah Wyle and Peter Coyote), Gregg Champion's action comedy The Cowboy Way (1994), in which she played Woody Harrelson's love interest, and had a small role as Capt. Alison Sinclair in Michael Bay's action comedy film starring Martin Lawrence and Will Smith, Bad Boys (1995). She also played Dr. Laura Baker, a molecular biologist, in Roger Donaldson's sci-fi thriller, Species (1995), and reprised the role in the sequel, Species II (1998).

During that time, TV viewers could also catch her in such television films Blind Vengeance, Lifetime’s Death Dreams, PBS’ historical documentary Not on the Frontline (as a narrator) and CBS’ In Sickness and in Health. Additionally, she was also seen opposite Bruno Kirby in I'll Be Waiting, a segment of Showtime's Fallen Angels helmed by Tom Hanks, and as a novelist on the ABC miniseries Stephen King's The Tommyknockers opposite Jimmy Smits. She was also seen in the CBS miniseries When Love Kills: The Seduction of John Hearn and made her first collaboration with director Peter Weller in Showtime's Partners. After playing a recurring role as George Clooney's love interest on NBC's popular medical drama ER, Marg became David Caruso's sex-starved widow on Showtime’s Elmore Leonard's Gold Coast, helmed by Weller, and starred as a woman involved with Steven Segal in the 1997 action film Fire Down Below. She also starred as a talk show host on Murder Live and portrayed the furious sibling to Steven Weber's character on Showtime's miniseries about the elusive Gulf War Syndrome, Thanks of a Grateful Nation. She also starred opposite Ann-Margret in Showtime's Happy Face Murders. Helgenberger scored another big break when she snagged the co-starring role of Catherine Willows, a former show girl employed as a blood spatter analyst on the popular Emmy Award-winning CBS drama CSI: Crime Scene Investigation. Her performance as the female lead has earned her two Emmy Award and two Golden Globe nominations. In 2005, she and her fellow cast members won the Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Drama Series.

When CSI first started filming, Helgenberger visited the Clark County Coroner’s Office to see how things were really done. She even viewed autopsies that were being performed. Helgenberger has stated that she was angered at the franchising of CSI. She says that she often plays hacky sack with the guys during their free time on set. Helgenberger got the chance to act with her husband, Alan Rosenberg, again when he guest starred on CSI, Season 5 ("Weeping Willows") and Season 7 ("Leaving Las Vegas"). During her hefty stint on the hit show, Marg supported Julia Roberts in the true story-based, Oscar-winning film Erin Brockovich and portrayed Patsy Ramsey in the CBS miniseries about the mysterious murder of 6-year-old beauty pageant contestant JonBenét Ramsey in Perfect Murder, Perfect Town. She also starred as Dennis Quaid’s wife and Scarlett Johansson’s mother in writer-director Paul Weitz's romantic drama comedy In Good Company (2004) and appeared on Pond's Smooth Perfection Skin Cream 2005 print ad. Recently, on June 1, 2007, Marg's latest film, Mr. Brooks, was released. In the gripping suspense thriller directed by Bruce A. Evans, she co-stars as the beautiful, loving wife to Kevin Costner. Demi Moore, William Hurt and Dane Cook also star in the film. About the film, Marg said, “It’s one of the only scripts I’ve read in my life that I really didn’t think I could put down. It has style, suspense, thrills and the characters really get under your skin because they are such complicated and tortured souls.”

Marg is currently filming writer-director Charles Burmeister's upcoming thriller, Columbus Day, starring Val Kilmer. In 2005, Universal Studios submitted Helgenberger in the best supporting actress category for the Oscars for her performance as Ann Foreman in her 2004 movie In Good Company. In 2007, she was featured in the movies Conan: Red Nails (as the voice of Princess Tascela) and Mr. Brooks. In Mr. Brooks her character's daughter is played by Danielle Panabaker, the sister of Kay Panabaker, who plays Catherine Willow's daughter on CSI. In mid 2006, Helgenberger’s hometown of North Bend, Nebraska, population 1213, renamed the street on which Helgenberger had her childhood home "Helgenberger Avenue." In animation, she lent her voice as Greek goddess Hera on DC Universe straight-to-video feature Wonder Woman, set for a March 3 release. While not appearing in-frame, she is the unrequited love interest of the bespectacled amphibian Buddy in Mark Heath's Spot the Frog comic strip. As of May 15, 2008, she has renewed her CSI contract with CBS for 2 additional years.

• Conan: Red Nails (2009) (V) (in production) (voice) .... Princess Tascela
  
• "CSI: Crime Scene Investigation" .... Catherine Willows (199 episodes, 2000-2009)
  ... aka CSI: Las Vegas (South Africa: English title: informal alternative title) (USA: syndication title)
  ... aka C.S.I. (USA: short title)
  ... aka CSI: Weekends (USA: promotional title)
  ... aka Experts, Les (Canada: French title)
       - No Way Out (2009) TV episode .... Catherine Willows
       - Turn, Turn, Turn (2009) TV episode .... Catherine Willows
       - Kill Me if You Can (2009) TV episode .... Catherine Willows
       - Miscarriage of Justice (2009) TV episode .... Catherine Willows
       - Deep Fried and Minty Fresh (2009) TV episode .... Catherine Willows
        (194 more)
• Wonder Woman (2009) (V) (voice) .... Hera
• Columbus Day (2008) .... Alice
• Mr. Brooks (2007) .... Emma Brooks
• In Good Company (2004) .... Ann
• "King of the Hill" .... Mrs. Hanover / ... (1 episode, 2004)
       - Hank's Back (2004) TV episode (voice) .... Mrs. Hanover/Pretty Student
• CSI: Crime Scene Investigation - Dark Motives (2004) (VG) (voice) .... CSI Level 3 Catherine Willows
• CSI: Crime Scene Investigation (2003) (VG) (voice) .... Catherine Willows
• Erin Brockovich (2000) .... Donna Jensen
• Perfect Murder, Perfect Town: JonBenét and the City of Boulder (2000) (TV) .... Patsy Ramsey
• "Frasier" .... Emily (1 episode, 2000)
       - Out with Dad (2000) TV episode .... Emily